Familial hypercholesterolemia is an inherited disorder that results in high serum cholesterol levels attributable to an elevated level of cholesterol-carrying low-density lipoprotein (LDL). This condition leads to deposition of LDL-derived cholesterol in several tissues, especially tendons and arteries, which results in a high incidence of heart attack and ultimately death. Existing drug and plasma exchange therapies have significant drawbacks. We propose to explore the treatment of hypercholesterolemia with a membrane-immobilized enzyme system that removes cholesterol- carrying protein from to blood and returns the cleansed plasma to the patient. Plasma will be contacted with an LDL-degrading enzyme in order to render the LDL particles capable of being separated from the plasma, e.g., in a membrane filter. In Phase I, a knowledge base has been established that supports the technical feasibility of a plasma separator/bioreactor module for the extracorporeal removal of LDL. In Phase II, we will extend that knowledge base and construct and test prototype LDL-removal modules both in vitro and in animals. The purpose of this project is thus to demonstrate a novel and beneficial approach to enzymatic LDL removal, to create a new business opportunity in extracorporeal blood processing, and to address the medical needs of afflicted individuals who are poorly served by existing hypercholesterolemia therapies.